Substituted bicyclic alkoxy pyrazole analogs as allosteric modulators of mGluR5 receptors

Abstract

In one aspect, the invention relates to substituted bicyclic alkoxy pyrazole analogs, derivatives thereof, and related compounds, which are useful as positive allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5); synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating neurological and psychiatric disorders associated with glutamate dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

What is claimed is: 
     
       1. A compound having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein R 1  is aryl or heteroaryl and substituted with 0, 1, 2, or 3 groups each independently selected from cyano, halo, hydroxyl, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; 
         wherein each of R 2a  and R 2b  is independently selected from hydrogen and C1-C4 
         wherein R 3  is selected from hydrogen, halogen, cyano, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; 
         wherein each of R 4a  and R 4b  is hydrogen or C1-C4 alkyl; 
         wherein each of R 5a  and R 5b  is hydrogen or C1-C4 alkyl; 
         wherein each of R 6a  and R 6b  is hydrogen or C1-C4 alkyl; 
         wherein R 7  is selected from C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, hydroxy(C1-C8 alkyl), (C1-C6 alkyl)-O—(C1-C6 alkyl)-, (C1-C6 monohaloalkyl)-O—(C1-C6 alkyl)-, (C1-C6 polyhaloalkyl)-O—(C1-C6 alkyl)-, (C1-C6 alkyl)-NH—(C1-C6 alkyl)-, (C1-C6 alkyl)(C1-C6 alkyl)N—(C1-C6 alkyl)-, Cy 1 , Cy 1 -(C2-C6 alkyl)-, and Cy 1 -C(R 9a )(R 9b )—; and
 wherein Cy 1 , when present, is selected from C3-C8 cycloalkyl, C2-C7 heterocycloalkyl, phenyl, monocyclic heteroaryl, and bicyclic heteroaryl; and wherein Cy 1 , when present, is substituted with 0, 1, 2, or 3 non-hydrogen groups each independently selected from halo, cyano, —NH 2 , C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, mono(C1-C6 alkyl)amino, di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, and phenyl; 
 wherein each of R 9a  and R 9b  is independently selected from hydrogen, C1-C8 alkyl, C1-C8 monohaloalkyl, C1-C8 polyhaloalkyl, and C1-C8 alkoxy; 
 
         wherein each of R 8a  and R 8b  is hydrogen or C1-C4 alkyl; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       2. The compound of  claim 1 , wherein R l  is phenyl. 
     
     
       3. The compound of  claim 2 , wherein the phenyl is substituted with 0-1 groups selected from fluoro, cyano, methyl, and methoxy. 
     
     
       4. The compound of  claim 1 , wherein each of R 2a , R 2b , R 3 , R 5a , R 5b , and R 4b  are hydrogen, and wherein R 4a  is selected from hydrogen and methyl. 
     
     
       5. The compound of  claim 1 , wherein each of R 2a , R 2b , R 3 , R 4a , R 4b , and R 5b  are hydrogen, and wherein R 5a  is selected from hydrogen and methyl. 
     
     
       6. The compound of  claim 1 , wherein each of R 2a , R 2b , R 3 , R 4a , R 4b , R 5a , and R 5b  are hydrogen. 
     
     
       7. The compound of  claim 1 , wherein R 2a , R 2b , R 3 , R 4a , R 4b , R 5a , and R 5b , R 6a , and R 6b  are hydrogen. 
     
     
       8. The compound of  claim 1 , wherein Cy 1 , when present, is selected from phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrazolyl, 1-methyl-pyrazolyl, pyrrolyl, 1-methyl-pyrrolyl, thiophenyl, furanyl, 5-methylfuranyl, indolyl, 1-methylindolyl, indazolyl, 1-methylindazolyl, cyclopentyl, cyclobutyl, and cyclopropyl, and wherein Cy 1 , when present, is substituted with 0, 1, 2, or 3 groups each independently selected from halo, cyano, —NH 2 , C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, mono(C1-C6 alkyl)amino, di(C1-C6 alkyl)amino, C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, and phenyl. 
     
     
       9. The compound of  claim 8 , wherein Cy 1 , when present, is selected from phenyl, indazolyl, indolyl, thiophenyl, furanyl, 1-methylpyrrolyl, and cyclopentyl. 
     
     
       10. The compound of  claim 8 , wherein Cy 1 , when present, is selected from phenyl substituted with 0-2 groups independently selected from fluoro, chloro, cyano, methyl, trifluoromethyl, and methoxy. 
     
     
       11. The compound of  claim 1 , having a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
       12. The compound of  claim 1 , having a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
       13. The compound of  claim 1 , having a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
       wherein each of R 10a , R 10b , R 10c , R 10d , and R 10e  is independently selected from hydrogen, cyano, halo, hydroxyl, C1-C4 alkyl, C1-C4 alkyloxy, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl, provided that at least two of R 10a , R 10b , R 10c , R 10d , and R 10e  are hydrogen; or a pharmaceutically acceptable salt, thereof. 
     
     
       14. The compound of  claim 1 , having a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
       wherein each of R 4a , R 4b , R 5a , and R 5b  is independently selected from hydrogen and methyl;
 wherein each of R 10a , R 10b , R 10c , R 10d , and R 10e  is independently selected from hydrogen, cyano, fluoro, methyl, and methoxy, provided that at least four of R 10a , R 10b ,R 10c , R 10d , and R 10e  are hydrogen; or a pharmaceutically acceptable salt, thereof. 
 
     
     
       15. The compound of  claim 1 , having a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
       wherein each of R 4a , R 4b , R 5a , and R 5b  is independently selected from hydrogen and methyl;
 wherein each of R 10a , R 10b , R 10c , R 10d , and R 10e  is independently selected from hydrogen, cyano, fluoro, methyl, and methoxy, provided that at least four of R 10a , R 10b , R 10c , R 10d , and R 10e  are hydrogen; wherein each of R 11a , R 11b , R 11c , R 11d , and R 11e  is independently selected from hydrogen, fluoro, chloro, cyano, methyl, trifluoromethyl, and methoxy, provided that at least three of R 11a , R 11b , R 11c , R 11d , and R 11e  are hydrogen; or a pharmaceutically acceptable salt, thereof. 
 
     
     
       16. A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
       17. The compound of  claim 1 , wherein R 3  is hydrogen. 
     
     
       18. The compound of  claim 1 , wherein each of R 6a  and R 6b  is hydrogen. 
     
     
       19. The compound of  claim 1 , wherein each of R 8a  and R 8b  is hydrogen. 
     
     
       20. The compound of  claim 1 , having a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
       21. The compound of  claim 1 , having a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
       22. The compound of  claim 1 , having a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
       23. The compound of  claim 1 , having a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
       24. The compound of  claim 1 , having a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
       25. The compound of  claim 1 , having a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
       26. The compound of  claim 1 , having a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
       27. The compound of  claim 1 , wherein R 1  is aryl or heteroaryl and substituted with 0, 1, 2, or 3 groups independently selected from cyano, halo, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl. 
     
     
       28. The compound of  claim 1 ,
 wherein R 1  is aryl or heteroaryl and substituted with 0, 1, 2, or 3 groups independently selected from cyano, halo, C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl; and 
 wherein each of R 2a R 2b ,R 3 , R 4a ,R 4b ,R 5a ,R 5b ,R 6a , R 6b ,R 8a , and R 8b  is hydrogen.